Method of treating depression with thiourea derivatives

ABSTRACT

A method of utilizing thiourea derivatives of the formulas ##STR1## wherein R, R 1 , R 2 , R 3  and X are as hereinafter described, as agents in the treatment of depression, is described.

This is a division, of application Ser. No. 891,862, filed Mar. 30,1978, which in turn is a Continuation of Ser. No. 763,172, filed Jan.27, 1977, now U.S. Pat. No. 4,096,276, issued June 20, 1978, which inturn is a division of Ser. No. 677,106, filed Apr. 15, 1976, nowabandoned.

BRIEF SUMMARY OF THE INVENTION

Thiourea derivatives of the formulas ##STR2## wherein R is lower alkyl;R₁ and R₂, independently, are halogen; R₃ is amino or piperidino; and Xis sulfur or imino; and addition salts thereof with pharmaceuticallyacceptable acids, are described. The compounds of formulas I and II areuseful as anti-hypertensive agents.

In another aspect, the invention relates to a method of treatinghypertension which comprises administering to a host requiring suchtreatment an effective amount of a compound of the formula ##STR3##wherein R₁ ' and R₂ ', independently, are hydrogen, halogen or loweralkyl; X is sulfur or imino; and R₃ is amino or piperidino, or acompound of formula II, or an addition salt thereof with apharmaceutically acceptable acid.

DETAILED DESCRIPTION OF THE INVENTION

As used herein, the term "lower alkyl" denotes a straight or branchedchain hydrocarbon of 1-7 carbon atoms, such as methyl, ethyl, propyl,butyl, isobutyl, pentyl, heptyl, and the like. The term "halogen"denotes fluorine, bromine and chlorine; chlorine is preferred. The term"lower alkanoyl" denotes a radical derived from an aliphatic carboxylicacid of 1 to 7 carbon atoms, for example, formyl, acetyl, propionyl, andthe like.

The invention comprises compounds of the formulas ##STR4## wherein R islower alkyl; R₁ and R₂, independently, are halogen; R₃ is amino orpiperidino; and X is sulfur or imino; and addition salts thereof withpharmaceutically acceptable acids.

Exemplary of the compounds of formulas I and II of the invention are:

1-(2-aminoethyl)-3-(2,6-dichlorophenyl)-thiourea;

1-(2-aminoethyl)-3-(2,6-dibromophenyl)-thiourea;

1-(2-aminoethyl)-3-(2,6-difluorophenyl)-thiourea;

1-(2-aminoethyl)-3-(2,6-dichlorophenyl)-2-methylthiopseudoureadihydrochloride;

1-(2,6-dichlorophenyl)-3-[2-(1-piperidino)ethyl]-2-thiourea;

1-(2-aminoethyl)-3-(2,6-dichlorophenyl)-guanidine; and the like.

The most preferred compound of the invention is1-(2-aminoethyl)-3-(2,6-dichlorophenyl)-thiourea.

The compounds of the invention can be prepared as hereinafter described.

A compound of formula I wherein X is sulfur, can be prepared by treatingthe corresponding compound of the formula ##STR5## wherein R₁ and R₂ areas previously described, which is a known compound, with ammoniumthiocyanate and benzoyl chloride, is an inert organic solvent, forexample, acetone, a chlorinated hydrocarbon such as chloroform,methylene chloride or the like, preferably at the reflux temperature ofthe reaction mixture. The reaction product is treated with an alkalimetal hydroxide, such as sodium hydroxide, to obtain a compound of theformula ##STR6## wherein R₁ and R₂ are as previously described.

Thereafter, a compound of formula V is converted to a compound of theformula ##STR7## wherein R₁ and R₂ are as previously described,according to known procedures, for example, by heating a compound offormula V at the reflux temperature of the reaction mixture in thepresence of a solvent, for example, a halobenzene, such aschlorobenzene. Upon evaporation of the solvent and crystallization ordistillation of the residue, a compound of formula VI is obtained.

Advantageously, a compound of formula IV can also be converted to acompound of formula VI directly by treatment with thiophosgene in asolvent, for example, a halobenzene such as chlorobenzene or the like,containing dimethylformamide, at the reflux temperature of the reactionmixture. Upon evaporation of the solvent and distillation of theresidue, the desired compound of formula VI is obtained.

A compound of formula VI is converted to a compound of the formula##STR8## wherein R₁, R₂ and R₃ are as previously described, by treatinga compound of formula VI with ethylenediamine or aminoethylpiperidine inan inert organic solvent, for example, benzene, tetrahydrofuran, analkanol such as ethanol or the like, methylene chloride or the like, atroom temperature or at the reflux temperature of the reaction mixture.The reaction product of formula Ia can be recovered either bycrystallization or by suitable extraction, for example, with ahalogenated hydrocarbon such as methylene chloride.

A compound of the formula ##STR9## wherein R, R₁, R₂ and R₃ are aspreviously described, can be obtained by treating a compound of formulaIa with an alkyl halide such as iodomethane in the presence of aninorganic acid, for example, a hydrohalic acid, such as hydrochloricacid, in an organic solvent, for example, an alkanol such as methanol.Conveniently, the reaction is carried out at the refluxing temperatureof the reaction mixture. The desired compound of formula II is recoveredby basification of the reaction mixture, for example, with an alkalimetal hydroxide such as sodium hydroxide or the like, and extractionwith a solvent, for example, a halogenated hydrocarbon such as methylenechloride or the like.

A compound of formula I wherein X is imino, can be prepared by treatingthe corresponding compound of the formula ##STR10## wherein R, R₁ and R₂are as previously described, with a lower alkanoyl ethylenediamine in aninert organic solvent, for example, an alkanol such as amyl alcohol, ata temperature in the range of from about 150° to about 200° C., toobtain a compound of the formula ##STR11## wherein R₁ and R₂ are aspreviously described, and R₄ is alkanoyl.

The resulting compound of formula VIII can be separated, upon cooling ofthe reaction mixture, by partitioning the reaction mixture between anaqueous alkali metal hydroxide such as sodium hydroxide, and ahalogenated hydrocarbon solvent such as methylene chloride, andrecovering the desired compound from the halogenated hydrocarbonsolvent.

A compound of formula VIII is deacylated by known procedures, forinstance, by treatment with an inorganic acid, for example, a hydrohalicacid such as hydrochloric acid or the like, at the reflux temperature ofthe reaction mixture to obtain a compound of the formula ##STR12##wherein R₁ and R₂ are as previously described, and R₃ ' is amino. Thedesired compound of formula Ib can be recovered by evaporation and, ifrequired, crystallization.

The compounds of formulas I and II above are basic compounds which formacid addition salts with inorganic or organic acids. Thus, they formpharmaceutically acceptable acid addition salts with bothpharmaceutically acceptable organic and inorganic acids, such as,hydrohalides, e.g., hydrochloride, hydrobromide, other mineral acidsalts, such as, sulfate, nitrate, phosphate and the like, alkyl- andmono-aryl sulfonates, such as, ethanesulfonate, toluenesulfonate,benzenesulfonate, or the like, other organic acids such as formate,tartrate, maleate, citrate, benzoate, salicylate, ascorbate, or thelike. Non-pharmaceutically acceptable acid addition salts of compoundsof formulas I and II above can be converted into pharmaceuticallyacceptable acid addition salts via conventional metathetic reactionswhereby the non-pharmaceutically acceptable anion is replaced by apharmaceutically acceptable anion; or alternatively, by neutralizing thenon-pharmaceutically acceptable acid addition salt and then reacting theso-obtained free base with a reagent yielding a pharmaceuticallyacceptable anion.

The present invention also relates to a method of reducing bloodpressure by administering to a host, i.e., a warm-blooded animalrequiring such treatment, an effective amount of a compound of theformula ##STR13## wherein R₁ ' and R₂ ', independently, are hydrogen,halogen or lower alkyl; X is sulfur or imino; and R₃ is amino orpiperidino, or an addition salt thereof with a pharmaceuticallyacceptable acid, or a compound of the formula ##STR14## wherein R islower alkyl; R₁ and R₂, independently, are halogen; and R₃ is amino orpiperidino, or an addition salt thereof with a pharmaceuticallyacceptable acid. The compounds of formula III, which are inclusive ofthe compounds of formula I, form acid addition salts with inorganic ororganic acids, as described above, for the compounds of formulas I andII.

Exemplary of the compounds of formula III, other than the encompassedcompounds of formula I, are1-(2-aminoethyl)-3-(2,3-dichlorophenyl)-thiourea,1-(2-aminoethyl)-3-(2-methyl-4-chlorophenyl)-thiourea, and the like.

The compounds of formula II and formula III, which includes thecompounds of formula I, and salts thereof, possess hypotensive activity,that is, reduce the blood pressure in warm-blooded animals, and aretherefore useful as anti-hypertensive agents in warm-blooded animals.

The anti-hypertensive activity of the compounds of the invention offormulas I and II, as well as those of formula III, which is inclusiveof the compounds of formula I, can be demonstrated in either geneticallyor deoxycorticosterone acetate/sodium chloride fed hypertensive rats12-15 weeks of age. For example, Doca-Na hypertension is induced inCharles River male rats weighing 170-210 grams by unilateral nephrectomyfollowed by subcutaneous implantation of a 25 mg. deoxycorticosteroneacetate pellet. Animals are placed in individual cages and receive 0.9%sodium chloride solution and rat chow diet ad libitum. Two weeks areallowed to elapse from the time of surgery for development ofhypertension, i.e., systolic blood pressure above 150 mmHg. Systolicblood pressure is measured indirectly from the tail of unanesthetizedrats (restrained in holders heated for 5-10 minutes at 37°-38° C.) usinga pneumatic pulse transducer (piezo-electric crystal and occludingcuff). The transducer and occluding cuff are coupled to a two-channelrecorder. Control readings are taken prior to drug and at 1, 3, 6 and 24hours post-drug. All test compounds are prepared in acacia solution (5%)and are orally administered to the test animals.

When 1-(2-aminoethyl)-3-(2,6-dichlorophenyl)thiourea, which hasdemonstrated an LD₅₀ of 750-775 mg/kg p.o. and LD₅₀ of 450-550 mg/kgi.p. in the mouse, is utilized in the above test procedure at a dose of10 mg/kg p.o., a decrease in the blood pressure of 73 mm/Hg and adecrease of 81 beats/minutes in the heart rate 6 hours afteradministration of the test substance are observed.

When 1-(2-aminoethyl)-3-(2,3-dichlorophenyl)thiourea, which hasdemonstrated an LD₅₀ of >1000 mg/kg p.o. and LD₅₀ of 450 mg/kg i.p. inthe mouse, is utilized the above test procedure at a dose of 10 mg/kgp.o., a decrease in the blood pressure of 51 mm/Hg and a decrease of 95beats/minutes in the heart rate 6 hours after administration of the testsubstance are observed.

The compounds of formulas I and II as well as the compounds of formulaIII, which is inclusive of the compounds of formula I, or salts thereofas herein described, can be incorporated into standard pharmaceuticaldosage forms, for example, they are useful for oral or parenteralapplication with the usual pharmaceutical adjuvant material, forexample, organic or inorganic inert carrier materials such as water,gelatin, lactose, starch, magnesium stearate, talc, vegetable oils,gums, polyalkylene-glycols, and the like. The pharmaceuticalpreparations can be employed in a solid form, for example, as tablets,troches, suppositories, capsules, or in liquid form, for example, assolutions, suspensions, or emulsions. Pharmaceutical adjuvant materialscan be added and include preservatives, stabilizers, wetting oremulsifying agents, salts to change the osmotic pressure or to act asbuffers. The pharmaceutical preparations can also contain othertherapeutically active substances.

A suitable pharmaceutical dosage unit contains from about 0.1 to 5 mg.of a compound of formula I and II, as well as a compound of formula III,or an equivalent amount of a pharmaceutically acceptable acid additionsalt thereof. Suitable oral dosage regimens in warm-blooded mammalscomprise from about 0.1 mg/kg. per day to about 5 mg/kg. per day.Suitable parenteral dosage regimens in warm-blooded mammals comprisefrom about 0.05 mg/kg. per day to about 2.5 mg/kg. per day. However, forany particular subject, the specific dosage regimen should be adjustedaccording to individual need and the professional judgement of theperson administering or supervising the administration of a compound offormula I or II, as well as a compound of formula III. It is to beunderstood that the dosages set forth herein are exemplary only and thatthey do not, to any extent, limit the scope or practice of thisinvention.

The compounds of formulas I and II, as well as the compounds of formulaIII, and their pharmaceutically acceptable acid addition salts, haveeffects qualitatively similar to those of catapress, known for itstherapeutic uses and properties. Thus, the compounds of this inventiondemonstrate a pattern of activity associated with antihypertensiveagents of known efficacy and safety.

The compounds of formulas I and II have central nervous system activity,including antidepressant activity. The antidepressant activity can bedemonstrated in warm-blooded animals. For example, six mice are treatedwith the test compound. One hour later a ptosis-inducing dose oftetrabenazine (normally 150 mg/kg) is given intraperitoneally. Ptosis isread one hour after the tetrabenazine injection. The ED₅₀ is the dose atwhich ptosis is prevented in 3/6 of the mice. The numbers of miceexhibiting ptosis are counted. The ED₅₀ is calculated by the method ofBehrens. Arch. Exp. Path. & Pharm. 140, 237 (1929).

When 1-(2-aminoethyl)-3-(2,6-dichlorophenyl)-thiourea is utilized as thetest compound in the above procedure, it demonstrates an ED₅₀ of 5.7mg/kg.

The following Examples further illustrate the invention. Alltemperatures are in degrees Centigrade, unless otherwise stated.

EXAMPLE 1 Preparation of 1-(2-aminoethyl)-3-(2,6-dichlorophenyl)thiourea

To an ice cold solution of 350 ml. of ethylenediamine in 150 ml. oftetrahydrofuran was added a solution of 50.0 g. of2,6-dichlorophenylisothiocyanate in 150 ml. of tetrahydrofuran over aperiod of 4 hours. The resulting solution was stirred overnight at roomtemperature and concentrated. The product was partitioned between 1 l.of 1 N hydrochloric acid and 600 ml. of methylene chloride. The aqueouslayer was extracted at 2×300 ml. of methylene chloride, made basic with4 N sodium hydroxide, and extracted 3×500 ml. of methylene chloride. Thecombined base extracts were washed 1×100 ml. of water, dried overpotassium carbonate and concentrated to give 53.8 g. (83%) of1-(2-aminoethyl)-3-(2,6-dichlorophenyl)thiourea, m.p. 136°-138°.Recrystallization from ethyl acetate gave the analytical sample, m.p.135°-137°.

EXAMPLE 2 Preparation of 1-(2,6-dichlorophenyl)thiourea

A dry 500 ml. flask was charged with a solution of 17 g. of ammoniumthiocyanate in 100 ml. of acetone, and 23.3 ml. of benzoyl chloride wasadded over a period of 5 minutes. On completion of the addition, themixture was refluxed for 5 minutes, and upon cooling, a solution of 320g. of 2,6-dichloroaniline in 100 ml. of acetone was added over a10-minute period. After stirring for 10 minutes, the reaction mixturewas poured onto 1.5 l. of water, and the yellow precipitate wascollected. This material was suspended in 300 ml. of 10% sodiumhydroxide, which was heated to reflux for 15 minutes and filtered hot togive 369.2 g. (85%) of 1-(2,6-dichlorophenyl)thiourea, m.p. 158°-160°.

EXAMPLE 3 Preparation of 2,6-dichlorophenylisothiocyanate

A solution of 156.9 g. of 1-(2,6-dichlorophenyl)thiourea in 1 l. ofchlorobenzene was refluxed for 20 hours and concentrated. The resultingoil was triturated with 1 l. of hot hexane which was filtered. Oncooling overnight, 52 g. (36%) of 2,6-dichlorophenylisothiocyanate, m.p.41°-42° separated. Concentration of the filtrate gave an additional 64.2g. (44%), m.p. 41°-43° in two crops. Recrystallization of a sample fromhexane gave the analytical sample, m.p. 41°-42°.

This substance can also be prepared as follows:

A solution of 800 g. of 2,6-dichloroaniline in 3.2 l. of chlorobenzene,69 ml. of dimethylformamide and 708 ml. of thiophosgene was heatedslowly as the reaction mixture foamed, to 110°. After 30 minutes at110°, the mixture was cooled to 70°, filtered through a pad of silicagel and concentrated to dryness. The resulting oil was distilled to give947 g. (94%) of 2,6-dichlorophenylisothiocyanate, bp 100°/0.3 mm, m.p.41°-42°.

EXAMPLE 4 Preparation of1-(2-aminoethyl)-3-(2,6-dichlorophenyl)-2-methylthiopseudoureadihydrochloride

A solution of 12.68 g. of1-(2-aminoethyl)-3-(2,6-dichlorophenyl)thiourea in 80 ml. of ethanol,4.0 ml. of concentrated hydrochloric acid and 12 ml. of iodomethane wasrefluxed for 2 hours. On cooling, the mixture was poured onto 200 ml. ofwater and sufficient 4 N sodium hydroxide was added to bring the pH to11. The aqueous solution was extracted 3×150 ml. of methylene chloride,and the combined organic layers were washed 1×100 ml. of water, driedover potassium carbonate and concentrated. The resulting gum gave asolid on standing, i.e.,1-(2-aminoethyl)-3-(2,6-dichlorophenyl)-2-methylthiopseudourea, m.p.74°-79°, whose spectral data were consistent with the assignedstructure. The material was too labile for purification and wasacidified with hydrochloric acid and crystallized from ethanol-ether togive 14.10 g. (84%) of1-(2-aminoethyl)-3-(2,6-dichlorophenyl)-2-methylthiopseudoureadihydrochloride, m.p. 179°-184°. Two crystallizations from ethanol-ethergave an analytical sample, m.p. 179°-182°.

EXAMPLE 5 Preparation of 1-(2-aminoethyl)-3-(2,6-dibromophenyl)thiourea

In a similar manner to that described in Example 1, ethylenediamine wasreacted with 2,6-dibromophenylisothiocyanate to yield1-(2-aminoethyl)-3-(2,6-dibromophenyl)thiourea, melting point 155°-157°.

EXAMPLE 6 Preparation of 1-(2,6-dibromophenyl)thiourea

A solution of 4.6 ml. of benzoyl chloride in 10 ml. of acetone was addedover a period of 5 minutes to a solution of 3.32 g. of ammoniumthiocyanate in 60 ml. of dry acetone at reflux. The resulting solutionwas refluxed for 10 minutes and a solution of 10.0 g. of2,6-dibromoaniline in 40 ml. of acetone was added over a period of 10minutes. After 15 minutes at reflux, the reaction mixture was pouredonto 300 ml. of water and filtered. The resulting solid was suspended in30 ml. of 10% sodium hydroxide and boiled for 10 minutes. The clearsolution was acidified, neutralized to pH 8 with ammonia and filtered,giving 12.0 g. (97%) of 1-(2,6-dibromophenyl)thiourea, m.p. 186°-189°.Recrystallization from aqueous methanol gave the analytical sample, m.p.192°-193°.

EXAMPLE 7 Preparation of 2,6-dibromophenylisothiocyanate

A suspension of 101 g. (0.326 mole) of 1-(2,6-dibromophenyl)thiourea in1 l. of chlorobenzene was stirred and refluxed 20 hours, and theresulting solution was filtered and evaporated. The tan solid obtainedwas triturated with boiling petroleum ether and filtered. On cooling,the filtrate deposited 63.4 g. of yellow needles of2,6-dibromophenylisothiocyanate, m.p. 63°-65°. A portion wasrecrystallized from ether-petroleum ether to give the analytical sample,m.p. 65°-66°.

EXAMPLE 8 Preparation of 1-(2-aminoethyl)-3-(2,6-difluorophenyl)thiourea

A solution of 11.1 g. of 2,6-difluorophenylisothiocyanate in 30 ml. oftetrahydrofuran was added to an ice cold solution of 100 ml. of ethylenediamine in 100 ml. of tetrahydrofuran over the course of 10 minutes. Thereaction mixture was stirred overnight at room temperature, concentratedin vacuo, and partitioned between 50 ml. of methylene chloride and 200ml. of water. The aqueous layer was extracted 2×50 ml. methylenechloride and the combined organic layers were dried over potassiumcarbonate and evaporated to a foam which on trituration withethanol-water gave 1.06 g. (8%) of1,1-ethylenebis-[3-(2,6-difluorophenyl)-2-thiourea]. Tworecrystallizations from ethanol-water gave an analytical sample, m.p.200°-204°.

The aqueous layer from above was evaporated to 14.8 g. of a brown oilwhich was dissolved in water and passed through a column of 300 ml. ofDowex-50-W cation exchange resin in the H⁺ form. Elution with 500 ml.portions of water, 20% aqueous pyridine, and 20% aqueous triethylaminegave only traces of unidentified material. Further elution with 800 ml.of 1:1:3 triethylamine-ethanol-water gave an oil which was acidifiedwith succinic acid and crystallized from ethanol-ether to give 9.83 g.of the succinate salt of1-(2-aminoethyl)-3-(2,6-difluorophenyl)thiourea, m.p. 74°-79°. Thefiltrate gave an additional 0.93 g., m.p. 68°-75°. Recrystallizationfrom ethanol-ether gave the analytical sample, m.p. 80°-84°.

EXAMPLE 9 Preparation of 2,6-difluorophenylisothiocyanate

A suspension of 11.0 g. of 2,6-difluoroaniline in 100 ml. of 1 Nhydrochloric acid and 50 ml. of methylene chloride was stirredmechanically as 6.8 ml. of thiophosgene was added. After remaining forthree hours at room temperature, the layers were separated, and theaqueous phase was extracted 2×100 ml. of methylene chloride. Thecombined organic layers were washed 1×50 ml. of water, dried overmagnesium sulfate and evaporated. The resulting oil was distilled, andthe fraction boiling 160°-165°, 100 mm was collected, and yielded 11.1g. (78%) of 2,6-difluorophenylisothiocyanate.

EXAMPLE 10 Preparation of1-(2-aminoethyl)-2-(2,6-dichlorophenyl)guanidine dihydrochloride

A solution of 16.57 g. of1-(2-acetylaminoethyl)-2-(2,6-dichlorophenyl)-guanidine in 150 ml. ofconcentrated hydrochloric acid was refluxed for 16 hours and wasconcentrated under reduced pressure. Trituration with ethanol gave 24.06g. of a white solid which was recrystallized from aqueous ethanol-etherto give 14.18 g. (77%) of1-(2-aminoethyl)-2-(2,6-dichlorophenyl)guanidine dihydrochloride, m.p.154°-160° partly melt, 222°-224° clear. On addition of ether, thefiltrate gave an additional 4.81 g. (26%) m.p. 155°-160° partly melt,221°-224° clear.

EXAMPLE 11 Preparation of1-(2-acetylaminoethyl)-2-(2,6-dichlorophenyl)guanidine

A solution of 45.0 g. of 1-(2,6-dichlorophenyl)-2-methylthiopseudoureaand 44.75 g. of N-acetylethylenediamine in 35 ml. of amyl alcohol washeated at a bath temperature of 180° for 3 hours. On cooling, themixture was partitioned between 250 ml. portions of 1 N sodium hydroxideand methylene chloride. The aqueous layer was extracted 2×250 ml. ofmethylene chloride and the combined organic layers were washed with1×200 ml. water, dried (K₂ CO₃), and evaporated to an oil. Triturationwith ether gave 16.56 g. (46%) of1-(2-acetylaminoethyl)-2-(2,6-dichlorophenyl)guanidine, m.p. 186°-193°.

Further addition of ether to the filtrate gave an additional 1.01 g.(3%), m.p. 184°-193°. Two crystallizations from methylenechloride-hexane gave the analytical sample m.p. 196°-198°.

EXAMPLE 12 Preparation of1-(2,6-dichlorophenyl)-3-[2-(1-piperidino)ethyl]-2-thiourea

In a similar manner to that described in Example 1,1-(2-aminoethyl)-piperidine was reacted with2,6-dichlorophenyl-isothiocyanate to yield directly (without extraction)1-(2,6-dichlorophenyl)-3-[2-(1-piperidino)ethyl]-2-thiourea, meltingpoint 165°-168°. The hydrochloride salt melts at 205°-208°.

EXAMPLE 13

    ______________________________________                                        Tablet Formulation                                                            Ingredient             mg/tablet                                              ______________________________________                                        1-(2-aminoethyl)-3-(2,6-dichlorophenyl)-                                      thiourea               1.00                                                   Lactose Anhydrous      137.00                                                 Microcrystalline Cellulose                                                                           40.00                                                  Cornstarch             20.00                                                  Magnesium Stearate     2.00                                                   Weight of Tablet       200.00   mg.                                           ______________________________________                                    

Procedure:

A premix of 1 part of 1-(2-aminoethyl)-3-(2,6-dichlorophenyl)-thioureaand part of 137 parts of anhydrous lactose is prepared and milled. Theremaining lactose is added to the premix, as well as 40 parts ofmicrocrystalline cellulose and 20 parts of cornstarch, and milled for 15minutes. To this is added 2 parts of magnesium stearate with mixing for2 minutes. Tablets are prepared by compression on a suitable punch.

EXAMPLE 14

    ______________________________________                                        Table Formulation                                                             Ingredients             mg/tablet                                             ______________________________________                                        1-(2-aminoethyl)-3-(2,6-dichlorophenyl)-                                      thiourea                1.00                                                  Lactose Hydrous         162.00                                                Modified Starch         15.00                                                 Pregelatinized Starch   20.00                                                 Magnesium Stearate      2.00                                                  Weight of Tablet        200.00                                                ______________________________________                                    

Procedure:

A premix of one part of 1-(2-aminoethyl)-3-(2,6-dichlorophenyl)-thioureaand part of 162 parts of hydrous lactose is prepared and milled. Theresulting mixture is mixed with the remainder of the hydrous lactose, 15parts of modified starch and 20 parts of pregelatinized starch andgranulated with water. The resulting granulation is dried overnight,milled and mixed with 2 parts of magnesium stearate. Tablets areprepared by compression on a suitable punch.

EXAMPLE 15

    ______________________________________                                        Capsule Formulation                                                           Ingredients             mg/capsule                                            ______________________________________                                        1-(2-aminoethyl)-3-(2,6-dichlorophenyl)-                                      thiourea                1.00                                                  Lactose Hydrous         163.00                                                Cornstarch              30.00                                                 Talc                    5.00                                                  Magnesium Stearate      1.00                                                  Weight of Capsule       200.00                                                ______________________________________                                    

Procedure:

A premix of one part of 1-(2-aminoethyl)-3-(2,6-dichlorophenyl)-thioureaand part of 163 parts of hydrous lactose is prepared and milled.Thereafter, the remaining lactose and 30 parts of cornstarch are addedto the milled mixture and mixed well. Subsequently, 5 parts of talc and1 part of magnesium stearate are added and the entire batch is mixed for5 minutes and encapsulated in hardshell capsules.

We claim:
 1. A method of treating depression which comprisesadministering to a host requiring such treatment an effective amount ofa thiourea derivative of the formula ##STR15## wherein R is lower alkyl;R₁ and R₂, independently, are halogen; R₃ is amino or piperidino; and Xis sulfur or imino, or an addition salt thereof with a pharmaceuticallyacceptable acid.
 2. A method in accordance with claim 1, wherein thethiourea derivative is 1-(2-aminoethyl)-3-(2,6-dichlorophenyl)-thiourea.